rs3895234

Variant names:

• chr11-35306278-A-G
• rs3895234
• NM_004171.4:c.562-36T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004171.4(SLC1A2):​c.562-36T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 1,557,256 control chromosomes in the GnomAD database, including 47,150 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3993 hom., cov: 31)
  • Exomes 𝑓: 0.24 (43157 hom.)
• Consequence: SLC1A2 NM_004171.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.03
• Publications: 6 publications found

Genes affected

SLC1A2 (HGNC:10940): (solute carrier family 1 member 2) This gene encodes a member of a family of solute transporter proteins. The membrane-bound protein is the principal transporter that clears the excitatory neurotransmitter glutamate from the extracellular space at synapses in the central nervous system. Glutamate clearance is necessary for proper synaptic activation and to prevent neuronal damage from excessive activation of glutamate receptors. Improper regulation of this gene is thought to be associated with several neurological disorders. Alternatively spliced transcript variants of this gene have been identified. [provided by RefSeq, Jun 2017]

SLC1A2 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 41

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen, G2P, Ambry Genetics
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 11-35306278-A-G is Benign according to our data. Variant chr11-35306278-A-G is described in ClinVar as Benign. ClinVar VariationId is 1332976.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.274 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004171.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC1A2	NM_004171.4	MANE Select	c.562-36T>C		intron	N/A	NP_004162.2
	SLC1A2	NM_001439342.1		c.550-36T>C		intron	N/A	NP_001426271.1
	SLC1A2	NM_001195728.3		c.535-36T>C		intron	N/A	NP_001182657.1	P43004-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC1A2	ENST00000278379.9	TSL:1 MANE Select	c.562-36T>C		intron	N/A	ENSP00000278379.3	P43004-1
	SLC1A2	ENST00000395750.6	TSL:1	c.550-36T>C		intron	N/A	ENSP00000379099.2	A0A2U3TZS7
	SLC1A2	ENST00000644779.1		c.673-36T>C		intron	N/A	ENSP00000494258.1	A0A2R8YD46

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33222 AN: 151680 Hom.: 3976 Cov.: 31

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.208

Gnomad AMR AF: 0.280

Gnomad ASJ AF: 0.205

Gnomad EAS AF: 0.215

Gnomad SAS AF: 0.0920

Gnomad FIN AF: 0.320

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.251

Gnomad OTH AF: 0.213

GnomAD2 exomes AF: 0.237 AC: 56272 AN: 237210 AF XY: 0.230

Gnomad AFR exome AF: 0.139

Gnomad AMR exome AF: 0.307

Gnomad ASJ exome AF: 0.215

Gnomad EAS exome AF: 0.213

Gnomad FIN exome AF: 0.327

Gnomad NFE exome AF: 0.254

Gnomad OTH exome AF: 0.255

GnomAD4 exome AF: 0.243 AC: 341855 AN: 1405460 Hom.: 43157 Cov.: 22 AF XY: 0.239 AC XY: 166602 AN XY: 697576

African (AFR) AF: 0.139 AC: 4458 AN: 31986

American (AMR) AF: 0.296 AC: 12550 AN: 42364

Ashkenazi Jewish (ASJ) AF: 0.213 AC: 5319 AN: 25012

East Asian (EAS) AF: 0.274 AC: 10661 AN: 38874

South Asian (SAS) AF: 0.104 AC: 8570 AN: 82472

European-Finnish (FIN) AF: 0.318 AC: 16201 AN: 51000

Middle Eastern (MID) AF: 0.191 AC: 1066 AN: 5582

European-Non Finnish (NFE) AF: 0.252 AC: 269985 AN: 1070140

Other (OTH) AF: 0.225 AC: 13045 AN: 58030

GnomAD4 genome AF: 0.219 AC: 33268 AN: 151796 Hom.: 3993 Cov.: 31 AF XY: 0.221 AC XY: 16368 AN XY: 74166

African (AFR) AF: 0.136 AC: 5619 AN: 41408

American (AMR) AF: 0.282 AC: 4293 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 709 AN: 3466

East Asian (EAS) AF: 0.215 AC: 1110 AN: 5160

South Asian (SAS) AF: 0.0912 AC: 439 AN: 4812

European-Finnish (FIN) AF: 0.320 AC: 3348 AN: 10478

Middle Eastern (MID) AF: 0.260 AC: 76 AN: 292

European-Non Finnish (NFE) AF: 0.251 AC: 17019 AN: 67910

Other (OTH) AF: 0.221 AC: 466 AN: 2112

Alfa AF: 0.225 Hom.: 753

Bravo AF: 0.216

Asia WGS AF: 0.187 AC: 648 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Developmental and epileptic encephalopathy, 41 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.098
DANN	Benign	0.22
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3895234;

hg19: chr11-35327825;

COSMIC: COSV53519634;

COSMIC: COSV53519634;